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A dimerization-dependent mechanism drives RAF catalytic activation

机译：二聚化依赖性机制驱动RAF催化活化

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摘要

The ERK (extracellular signal-regulated kinase) pathway is an evolutionarily conserved signal transduction module that controls cellular growth, differentiation and survival. Activation of receptor tyrosine kinases (RTKs) by the binding of growth factors initiates GTP loading of RAS, which triggers the initial steps in the activation of the ERK pathway by modulating RAF family kinase function. Once activated, RAF participates in a sequential cascade of phos-phorylation events that activate MEK, and in turn ERK. Unbridled signalling through the ERK pathway caused by activating mutations in RTKs, RAS or RAF has been linked to several human cancers. Of note, one member of the RAF family, BRAF, is the most frequently mutated oncogene in the kinase superfamily. Not surprisingly, there has been a colossal effort to understand the underlying regulation of this family of kinases. In particular, the process by which the RAF kinase domain becomes activated towards its substrate MEK remains of topical interest. Here, using Drosophila Schneider S2 cells, we demonstrate that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which we term the side-to-side dimer. Moreover, we find that the RAF-related pseudo-kinase KSR (kinase suppressor of Ras) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. We also show that RAF side-to-side dimer formation is essential for aberrant signalling by oncogenic BRAF mutants, and identify an oncogenic mutation that acts specifically by promoting side-to-side dimerization. Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis.
机译：ERK（细胞外信号调节激酶）途径是一种进化保守的信号转导模块，可控制细胞的生长，分化和存活。通过生长因子的结合激活受体酪氨酸激酶（RTK）会启动RAS的GTP加载，从而通过调节RAF家族激酶功能触发ERK途径激活的初始步骤。激活后，RAF会依次参与磷酸化事件的级联反应，从而激活MEK，进而激活ERK。由RTK，RAS或RAF中的活化突变引起的通过ERK途径的无限制的信号传导已经与几种人类癌症相关。值得注意的是，RAF家族的一个成员BRAF是激酶超家族中最常见的致癌基因。毫不奇怪，人们付出了巨大的努力来了解该激酶家族的潜在调控。特别地，RAF激酶结构域朝其底物MEK活化的过程仍然是局部关注的。在这里，我们使用果蝇施耐德S2细胞证明，RAF催化功能是响应其激酶结构域的特定二聚化模式（我们称为侧对侧二聚体）而受到调节的。此外，我们发现，RAF相关的假激酶KSR（Ras激酶抑制剂）也参与与RAF形成侧向异源二聚体，从而触发RAF活化。该机制为有关RAF催化活化的长期难题提供了优美的解释，也为KSR（尽管缺乏催化功能）直接介导RAF活化的能力提供了解释。我们还显示，RAF侧向二聚体形成对于由致癌性BRAF突变体引起的异常信号传导至关重要，并且可以识别出通过促进侧向对二聚化而具体起作用的致癌突变。总之，我们的数据将RAF的左右二聚体界面确定为干预BRAF依赖性肿瘤发生的潜在治疗靶标。

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  • 来源
    《Nature》 |2009年第24期|542-545|共4页
  • 作者

    Thanashan Rajakulendran; Malha Sahmi; Martin Lefrancois; Frank Sicheri; Marc Therrien;

  • 作者单位

    Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada Departement de pathologie et de biologie ceilulaire, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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